Triazole derivatives for use as antimycotic agents

ABSTRACT

Imidazole and triazole derivatives of the general formula ##STR1## in which Ar denotes thienyl or denotes phenyl, biphenylyl or naphthyl, each of which is substituted by halogen, lower alkyl or lower alkoxy, R 1  denotes hydrogen or lower alkyl, Alk denotes straight-chain or branched alkyl having 1 to 10 carbon atoms, Y denotes oxygen, sulfur, sulfinyl or sulfonyl, n denotes zero, 1 or 2, Z denotes oxygen, sulfur or sulfinyl, m denotes zero or 1, R 3  denotes hydrogen, straight-chain or branched alkyl, cyclohexyl, or denotes phenyl which is optionally substituted by hydroxyl, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or denotes biphenlyl, pyridyl or denotes naphthyl which is optionally substituted by halogen, X denotes CH or N, and R 2  denotes hydrogen or lower alkyl, and their pharmaceutically acceptable acid addition salts for use as antimycotic agents in human and veterinary medicine.

The invention relates to imidazole and triazole derivatives for use asantimycotic agents, and to the use of these compounds for thepreparation of antimycotic agents.

EP-A-183,147 describes β-substituted aminophenethylazole derivativeswhich are used as fungicides for agriculture and horticulture. It isdisclosed in H. Buchel: Fungicide Chemistry Advances and PracticalApplications, Am. Chem. Soc. Washington 1986, pages 11-23, and G. Jager,Pesticide Chemistry: Human Welfare and the Environment, vol. I, 55-56,Pergamon Press Oxford 1983, that despite great structrual similaritywithin the azole class of compounds there are often great differences inthe biological properties, and compounds effective as fungicides inagriculture are not necessarily suitable for use as antimycotics inhuman and veterinary medicine. Imidazole and triazole derivatives, someof which are new, have now been found and have excellent antimycoticproperties for use in human and veterinary medicine.

Accordingly, the invention relates to imidazole and triazole derivativesof the formula I ##STR2## in which Ar denotes thienyl or denotes phenyl,biphenylyl or naphthyl, each of which is substituted by halogen, loweralkyl or lower alkoxy, R₁ denotes hydrogen or lower alkyl, Alk denotesstraight-chain or branched alkylene having 1 to 10 carbon atoms, Ydenotes oxygen, sulfur, sulfinyl or sulfonyl, n denotes zero, 1 or 2, Zdenotes oxygen, sulfur or sulfinyl, m denotes zero or 1, R₃ denoteshydrogen, straight-chain or branched alkyl, cyclohexyl, or denotesphenyl which is optionally substituted by hydroxyl, halogen,trifluoromethyl, lower alkyl or lower alkoxy, or denotes biphenylyl,pyridyl or denotes naphthyl which is optionally substituted by halogen,X denotes CH or N, and R₂ denotes hydrogen or lower alkyl, and to theirpharmaceutically acceptable acid addition salts for use as antimycoticagents.

The substances according to the invention can be prepared by reactingcompounds of the formula II ##STR3## in which Ar and X have the abovemeaning, with compounds of the formula III

    R.sup.3 --(Z).sub.m --(CH.sub.2).sub.n --Y--Alk--NH.sub.2  (III)

in which R₃, Z, m, n, Y and Alk have the above meaning, whereappropriate in the presence of an inert diluent, reducing the resultingimino compounds of the formula IV ##STR4## in which Ar, Alk, Y, Z, R₂,R₃, n and m have the above meaning, where appropriate in the presence ofan inert diluent, and, if desired, converting the resulting compounds ofthe formula I in which R₁ denotes hydrogen, by customary alkylationmethods, into compounds of the formula I in which R₁ denotes loweralkyl.

Compounds II and III are reacted by, for example, heating the reactionmixture in an organic diluent. If compounds III are used in the form oftheir salts, then addition of one equivalent of a base, such astrialkylamine, sodium alcoholate or alkali metal hydroxide, isnecessary.

Diluents which are used are aliphatic or aromatic hydrocarbons, whichmay be chlorinated, such as petroleum fractions, perchloroethylene,benzene, toluene, chlorobenzene, xylene, ethers such as dibutyl ether ordioxane, alcohols such as butanol, pentanol or ethylene glycol, amidessuch as dimethylformamide, and mixtures thereof with the abovementioneddiluents. The components are heated under reflux with a water trap untilno more water of reaction separates out. The imino compound IV obtainedafter removal of the diluent is dissolved or suspended in an organicdiluent, followed by cooling. Diluents which are used are, inparticular, alcohols, preferably methanol, or ethers such as diethylether or tetrahydrofuran. The reduction is then carried out by additionof a reducing agent, in particular a complex metal hydride such as, forexample, alkali metal borohydride, alkali metal cyanoborohydride,aluminum borohydride or lithium aluminum hydride, preferably sodiumborohydride, at a temperature of, say, between -20° C. and the refluxtemperature of the diluent used, preferably at a temperature of -5° C.to +20° C.

All conventional methods of alkylation are suitable for introducing thealkyl radical R₁. For example, to introduce the methyl radical it ispossible to add aqueous formaldehyde solution to a compound of theformula I in which R₁ denotes hydrogen in an alcoholic, for examplemethanolic, solution, to heat the mixture to boiling, and, after thereaction solution has cooled, to allow a reducing agent, preferablysodium borohydride, to act on it.

In another process, the compounds of the general formula I are obtainedby reacting a compound of the general formula II with an aminoalkanol ofthe formula V

    NH.sub.2 --Alk--OH                                         (V)

reducing the imino compound which is obtained as reaction product of theformula VI ##STR5## converting the resulting hydroxyalkylamino compoundof the formula VII ##STR6## into the corresponding halogenoalkylaminocompound of the general formula VIII ##STR7## reacting the latter with acompound of the formula IX

    HY--(CH.sub.2).sub.n --(Z).sub.m --R.sup.3                 (IX)

and, if desired, converting the resulting compounds of the formula I inwhich R₁ denotes hydrogen, by customary alkylation methods, intocompound of the formula I in which R₁ denotes lower alkyl, where Ar,Alk, Y, Z, R₂, R₃, n and m in the above formulae V to IX have themeaning indicated for formula I, and Hal represents halogen.

The reaction of a compound of the formula II with an amino alcohol ofthe general formula V is carried out in an organic diluent at atemperature between 0° C. and 180° C., preferably at the refluxtemperature of the diluent used. The diluents which are used arealiphatic or aromatic hydrocarbons, which may be chlorinated, such aspetroleum fractions, perchloroethylene, benzene, toluene, xylene,chlorobenzene, ethers such as dibutyl ether or dioxane, alcohols such asbutanol, pentanol or ethylene glycol, amides such as dimethylformamide,and mixtures thereof with the abovementioned diluents. The iminocompound VI obtained after removal of the diluent is dissolved orsuspended in an organic diluent, and the solution or suspension iscooled. The diluents which are used are, in particular, alcohols,preferably methanol, or ethers such as diethyl ether or tetrahydrofuran.The reduction is carried out by addition of a reducing agent, preferablya complex metal hydride, in particular sodium borohydride, at atemperature from about -20° C. to the reflux temperature of the diluentused, preferably at a temperature of about -5° C. to +20° C. Thehydroxyalkylamino compound VII which is obtained after the customaryworking up is dissolved in an organic diluent, preferably in achlorinated aliphatic hydrocarbon, for example chloroform, and thesolution is cooled. The hydroxyl compound VII is converted into thecorresponding halogen compound VIII by addition of a halogenating agent,for example phosphorus tribromide, the reaction being carried out at atemperature of about -50° C. to room temperature, preferably from -20°C. to 0° C. The reaction of the compound of the general formula VIIIwith the compound of the general formula IX is preferably carried out inalcoholic, for example methanolic, solution in the presence of a base,for example sodium methylate or alkali metal hydroxide, at a temperatureof about -20° C. to 120° C., preferably at a temperature of 20° C. to80° C.

R₁ and R₂, independently of one another, in the formulae I to IX denotea hydrogen atom or an alkyl radical having 1 to 4 C atoms, preferably ahydrogen atom or the methyl radical. Ar denotes phenyl, biphenylyl,naphthyl or thienyl, each of which is substituted by halogen, loweralkyl or lower alkoxy, preferably 2,4-dichlorophenyl.

Alk denotes a straight-chain or branched, saturated hydrocarbon radicalhaving 1 to 10 C atoms. Examples of such radicals are methyl, ethyl,n-propyl, i-propyl, butyl, s-butyl, t-butyl radicals, and straight-chainor branched pentyl, hexyl, heptyl and octyl radicals.

Y denotes oxygen, sulfur, sulfinyl or sulfonyl, particularly preferablysulfur. Z can denote oxygen, sulfur or sulfinyl. R₃ denotes a hydrogenatom, a straight-chain or branched hydrocarbon radical having 1 to 12 Catoms, a cyclohexyl radical, phenyl or naphthyl radicals which can besub-stituted once or several times by halogen atoms, hydroxyl groups,alkyl or alkoxy radicals having 1-4 C atoms or trifluoromethyl, ordenotes biphenylyl or pyridyl, prefer-ably 4-chlorophenyl,4-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 4-methylphenyl, 2,4-, 3,4-or 2,6-di-chlorophenyl, 2-methyl-4-chlorophenyl, cyclohexyl or naphthyl.

The agents according to the invention have interesting antimycoticproperties and can be used as medicaments. This action has beendemonstrated by determination of the minimum inhibitory concentration(MIC) for yeasts, molds and dermatophytes.

The agents according to the invention can be used in the customarymanner as solid, semisolid or liquid formulations in the form oftablets, capsules, powders, suppositories, solutions, creams, lotions,gels, ointments or the like. Pharmaceutically tolerated non-toxicvehicles or excipients which are normally used for solid formulationsare tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc,gelatin, lactose and starch and the like. Examples of those suitable forsemisolid formulations are water, vegetable oils and low-boilingsolvents such as i-propanol, hydrogenated naphthalenes and the like.

The agents according to the invention can be subjected to conventionalpharmaceutical measures, such as sterilization, and can containconventional pharmaceutical additives such as preservatives,stabilizers, emulsifiers, salts for adjusting the osmotic pressure, andbuffers. The agents can also contain other therapeutically activematerials besides the compounds according to the invention.

The agents according to the invention are normally composed of apharmaceutically tolerated nontoxic vehicle in conjunction with one ormore compounds according to the invention in an effective amount whichresults in alleviation or prevention of the specific conditions to betreated. Since the active compounds according to the invention exhibitan antimycotic action over a wide concentration range, the effectiveamount may vary. For example, the amount for topical formulations may beapproximately 0.1 to 10% of the total pharmaceutical formulation,whereas in other formulations the amount may be approximately 5 to about95% or more. It is preferable, to facilitate administration, toformulate the pharmaceutical agents according to the invention as dosageunit.

The agents according to the invention can be administered forpharmaceutical use in humans and animals in a conventional manner, forexample: topically, orally, parenterally or in a similar manner. Theexact schedule for the pharmaceutical administration of the compoundsand agents according to the invention necessarily depends on therequirements of the individual case, the nature of the treatment, which,for example, may be preventive or curative, and the nature of theorganisms involved.

For systemic, for example oral or parenteral, administration, it isgenerally appropriate to administer the active compound in amounts ofabout 1-120 mg/kg of body weight per day, preferably 5-100 mg/kg of bodyweight per day, it also being possible to distribute these amounts overseveral doses (for example 3 per day) in order to achieve good results.However, for localized administration correspondingly less activecompound is necessary.

EXAMPLE 1 (Compound No. 1) (a) Preparation of the intermediate1-(2-(2,4-Dichlorophenyl)-2-(3-(4-bromophenylthio)propylimino)ethyl)-1H-imidazole

14.8 g (0.058 mole) of 2,4-dichlorophenacylimidazole, 16.8 g (0.059mole) of 4-bromophenylthiopropylamine hydrochloride and 6.0 g (0.059mole) of triethylamine are suspended or dissolved in 100 ml of toluene,and the mixture is heated under reflux with a water trap until no morewater of reaction separates out. The reaction solution is then washedwith water, the org. phase is dried with sodium sulfate and, after thesolvent has been evaporated off, 27.9 g of1-(2-(2,4-dichlorophenyl)-2-(3-(4-bromophenylthio)propylimino)ethyl)-1H-imidazoleare obtained as a viscous oil. (Yield: 98%).

(b) Preparation of the final product1-(2-(2,4-Dichlorophenyl)-2-(3-(4-bromophenylthio)propylamino)ethyl)-1H-imidazole

27.9 g (0.057 mole) of1-(2-(2,4-dichlorophenyl)-2-(3-(4-bromophenylthio)propylimino)ethyl)-1H-imidazoleare dissolved in 150 ml of methanol, the solution is cooled to -5° C.,and 6.4 g (0.169 mole) of sodium borohydride are added in portions insuch a way that the temperature does not rise above 5° C. The reactionmixture is subsequently stirred at 30° C. for a further 1 hour, thenevaporated to dryness and the pH is adjusted to 1 with half-concentratedhydrochloric acid. Subsequently the reaction solution is adjusted to apH of about 12 with 40% strength sodium hydroxide solution and isextracted several times with dichloromethane. After the combinedextracts have been washed with water and dried, and the solvent has beenremoved in vacuo there is obtained an oil from which, by treatment withacetone and nitric acid, 10.6 g of pure dinitrate of1-(2-(2,4-dichloro-phenyl)-2-(3-(4-bromophenylthio)propylamino)ethyl)-1H-imidazoleof melting point 162°-179° C. are obtained. (Yield: 32%).

EXAMPLE 2 (Compound No. 2) (a) Preparation of the intermediate1-(2-(2,4-Dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazole(Compound No. 50)

153.2 g (0.60 mole) of N-(2,4-dichlorophenacyl)imidazole and 53.0 g(0.705 mole) of 3-amino-1-propanol are suspended or dissolved in 400 molof toluene, and the mixture is heated under reflux with a water trapuntil no more water of reaction separates out. The reaction solution isthen washed 3 times with water, the organic phase is dried with sodiumsulfate and, after the solvent has been evaporated off, 179 g of1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazoleare obtained as a highly viscous oil. (Yield: 95.6%).

1-(2-(2,4-Dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazole

179.0 g (0.5737 mole) of1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazoleare dissolved in 300 ml of methanol, the solution is cooled to 0° C.,and 50.0 g (1.322 mole) of sodium borohydride are added in portions insuch a way that the temperature does not rise above 5° C. After theborohydride has been added, the reaction mixture is stirred at roomtemperature for a further 2 hours, then evaporated to dryness, and thepH is adjusted to 1 with half-concentrated hydrochloric acid.Subsequently, the reaction solution is adjusted to a pH of about 12 with40% strength sodium hydroxide solution, and is extracted several timeswith dichloromethane. After the combined organic extracts have beenwashed with water and dried, and the solvent has been removed in vacuo,169 g of crude product are obtained as an oil. Recrystallization of theoil from acetone results in 107 g of pure1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazole ofmelting point 77°-79° C. (Yield: 51%).

1-(2-(2,4-Dichlorophenyl)-2-(3-bromopropylamino)ethyl)-1H-imidazole

12.6 g (0.04 mole) of1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazoleare dissolved in 30 ml of chloroform, and the solution is cooled to -5°C. While stirring, 10.83 g of phosphorus tribromide, dissolved in 20 mlof CHCl₃, are slowly added dropwise in such a way that the temperaturedoes not rise above 0° C. After the dropwise addition, 100 ml ofpetroleum ether are added to the reaction mixture, resulting in 20.5 gof crystalline1-(2-(2,4-dichlorophenyl)-2-(3-bromopropylamino)ethyl)-1H-imidazole asthe dihydrobromide of melting point 140°-150° C., and this isimmediately reacted further, for reasons of stability. (Yield: 95%).

(b) Preparation of the final product1-(2-(2,4-Dichlorophenyl)-2-(3-(4-chlorophenylthio)propylamino)-1H-imidazole

5.4 g (0.01 mole) of freshly prepared1-(2-(2,4-dichlorophenyl)-2-(3-bromopropylamino)ethyl)-1H-imidazoledihydrobromide and 1.45 g (0.01 mole) of 4-chlorothiophenol aredissolved in 50 ml of methanol, and 6 ml of a 30% strength solution ofsodium methylate are added. The reaction mixture is heated to reflux for2 hours and then stirred at room temperature for a further 14 hours.Subsequently the methanol is evaporated off in vacuo, the residue istaken up in dichloromethane, and the organic phase is shaken with 5%strength sodium hydroxide solution and washed with water. After dryingand removal of the solvent in vacuo, the residue is dissolved inacetone, and concentrated nitric acid is added dropwise, resulting in3.0 g of1-(2-(2,4-dichlorophenyl)-2-(3-(4-chlorophenylthio)propylamino)ethyl)-1H-imidazoleas the dinitrate. Recrystallization from alcohol results in 2.2 g ofcolorless crystals of melting point 168°-177° C. (Yield: 41%).

EXAMPLE 3 (Compound No. 3): Preparation of the N-alkyl compounds1-(2-(2,4-Dichlorophenyl)-2-(N-methyl-3-(4-chlorobenzylthio)propylamino)ethyl)-1H-imidazole

8.18 g (0.018 mole) of1-(2-(2,4-dichlorophenyl)-2-(3-(4-chlorobenzylthio)propylamino)ethyl)-1H-imidazoleare dissolved in 100 ml of methanol, 34.3 g of 35% strength aqueousformaldehyde solution are added, and the mixture is boiled for 2 hours.The reaction solution is cooled and then 14.6 g of sodium borohydrideare added, and the mixture is stirred at room temperature of 14 hours.Subsequently the methanol is evaporated off in vacuo, half-concentratedhydrochloric acid is added to the residue, and then 40% strength sodiumhydroxide solution is added until the pH is 12, and the mixture isextracted 3 times with dichloromethane. The combined extracts are washedwith water and then the solvent is evaporated off in vacuo, resulting inan oil. The crude product is chromatographed on silica gel (mobilephase: ethyl acetate/methanol=10:1). An oil is obtained and is treatedwith ethanolic hydrochloric acid to result in 2.0 g of1-(2-(2,4-dichlorophenyl)-2-(N-methyl-3-(4-chlorobenzylthio)propylamino)ethyl)-1H-imidazole as the dihydrochloride of melting point 170°-180° C. (Yield:21%).

The following compounds were obtained by one of the indicated processes:

                                      TABLE I                                     __________________________________________________________________________    R.sub.2 = H                                                                                                                           Melting point         No. Ar        R.sub.1                                                                          Alk     Y  n Z  R.sub.3    X   Salt    °C.            __________________________________________________________________________    4   2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- H          N   --       98                   5   2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- H          CH--        viscous oil           6   2,4-dichlorophenyl                                                                      H  i-propylene                                                                           O  --                                                                              -- H          CH--        viscous oil           7   2,4-dichlorophenyl                                                                      H  i-butylene(2)                                                                         O  --                                                                              -- H          CH--        oil                   8   2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  2 O  H          N   --      77-78                 9   2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  2 O  H          CH--        oil                   10  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- phenyl     CH2HCl      140-145               11  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- phenyl     N   2HNO.sub.3                                                                            163-166               12  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-fluorophenyl                                                                           N   2HNO.sub.3                                                                            163-188               13  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-fluorophenyl                                                                           CH2HNO.sub.3                                                                              148-168               14  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           N   HCl     155-158               15  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      219-222               16  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-bromophenyl                                                                            N   2HNO.sub.3                                                                            147-152               17  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 4-bromophenyl                                                                            CH2HCl       200-210              18  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 2,4-dichlorophenyl                                                                       CHHCl       resin                 19  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 2,4-dichlorophenyl                                                                       CH2HCl      resin                 20  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  --                                                                              -- 3,4-dichlorophenyl                                                                       CHH.sub.2 C.sub.2 O.sub.4.                                                                185-187                                                           1/2H.sub.2 O                      21  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  2 S  4-chlorophenyl                                                                           N   HNO.sub.3.H.sub.2                                                                     148-157               22  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  2 S  4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              81-85                 23  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 2-methylpropyl                                                                           N   2HNO.sub.3                                                                            146-153               24  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 2-methylpropyl                                                                           CHH.sub.2 C.sub.2 O.sub.4                                                                 185- 195              25  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- dodecyl    N   2HNO.sub.3                                                                            111-125               26  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- dodecyl    CH2HNO.sub.3                                                                              122-124               27  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- cyclohexyl N   2HNO.sub.3                                                                            158-171               28  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- cyclohexyl CH2HNO.sub.3                                                                              149-160               29  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- p-tolyl    N   --      viscous oil           30  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- p-tolyl    N   2HNO.sub.3                                                                            134-149               31  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N   --      79-82                  32 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl.H.sub.2 O                                                                          124-127               33  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N   2HCl    145-149               34  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      206-212               35  2,4-dichlorophenyl                                                                      H  i-butylene(2)                                                                         S  --                                                                              -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              143-147               36  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-bromophenyl                                                                            N   2HNO.sub.3                                                                            154-165               37  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-bromophenyl                                                                            CH2HNO.sub.3                                                                              183-186               38  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-methoxyphenyl                                                                          N   HCl     135-145               39   2,4-dichlorophenyl                                                                     H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 4-methoxyphenyl                                                                          CH2HNO.sub.3                                                                              168-174               40  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  --                                                                              -- 2-naphthyl CH2HNO.sub.3                                                                              188-195               41  4-biphenylyl                                                                            H  --(CH.sub.2).sub.2 --                                                                 S  1 -- phenyl     N   --      viscous oil           42  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  1 -- phenyl     N   2HNO.sub.3                                                                            120-128               43  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  1 -- phenyl     CH2H.sub.2 C.sub.2 O.sub.4.                                                               156                                                               H.sub.2 O                         44  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  1 -- phenyl     CH--        viscous oil           45  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  1 -- 4-chlorophenyl                                                                           N   2HNO.sub.3                                                                            152-153               46  2,4-dichlorophenyl                                                                      H  --(CH.sub. 2).sub.2 --                                                                S  1 -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              157-161               47  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 S  1 -- 4-trifluoromethyl-                                                                       CH--        viscous oil                                            phenyl                                       48  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.2 --                                                                 O  2 SO 4-chlorophenyl                                                                           CH--        resin                 49  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- H          N--         81-83                 50  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- H          CH--        77-79                 51  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- phenyl     H   2HNO.sub.3                                                                            175-188               52  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- p-tolyl    N   2HNO.sub.3                                                                            130-140               53  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- p-tolyl    CH2HNO.sub.3                                                                              185-200               54  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-t-butylphenyl                                                                          N   2HCl    133-141               55  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-t-butylphenyl                                                                          CH2HCl      193-203               56  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-fluorophenyl                                                                           CH2HNO.sub.3                                                                              152-160               57  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           N   HCl     185-191               58  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           CH--        oil                   59  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      212-217               60  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      210-215               61  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-bromophenyl                                                                            N   HCl     178-188               62  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-bromophenyl                                                                            N   2HCl    193-200               63  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-bromophenyl                                                                            CH2HCl      215-220               64  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-iodophenyl                                                                             N   2HNO.sub.3                                                                            143-159               65  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-iodophenyl                                                                             CH2HNO.sub.3                                                                              188-190               66  2,4-dichlorophenyl                                                                      CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-methoxyphenyl                                                                          N   2HNO.sub.3                                                                            123-128               67  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-methoxyphenyl                                                                          CH2HNO.sub.3                                                                              168-188               68  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chloro-2-                                                                              N   2HNO.sub.3                                                                            151-157                                                methylphenyl                                 69  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 4-chloro-2-                                                                              CH2HNO.sub.3                                                                              169-186                                                methylphenyl                                 70  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 2,4-dichlorophenyl                                                                       N   HCl     viscous oil           71  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 2,4-dichlorophenyl                                                                       CH2HCl      203-207               72  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 2,6-dichlorophenyl                                                                       N   2HNO.sub.3                                                                            176-188               73  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 2,6-dichlorophenyl                                                                       CH2HCl      191-193               74  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 2,6-dichlorophenyl                                                                       CH2HCl      191-127               75  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- biphenyl   N   2HNO.sub.3                                                                            144-155               76  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- biphenyl   CH2HNO.sub.3                                                                              194 (decom-                                                                   position)             77  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 6-bromo-2-naphthyl                                                                       N   2HNO.sub.3                                                                            197-198               78  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 6-bromo-2-naphthyl                                                                       CH2HNO.sub.3                                                                              199-203               79  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- 6-bromo-2-naphthyl                                                                       CH2HCl      190-195               80  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-methyl-2-butyl                                                                         N   2HNO.sub.3                                                                            152-158               81  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-methyl-2-butyl                                                                         CHH.sub.2 C.sub.2 O.sub.4                                                                 178-181               82  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- octyl      N   2HNO.sub.3                                                                            124-125               83  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- octyl      CH2HNO.sub.3                                                                              164-170               84  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- dodecyl    N   2HNO.sub.3                                                                            121-123               85  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- dodecyl    CH2HNO.sub.3                                                                              118-143               86  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- cyclohexyl N   2HNO.sub.3                                                                            158                   87  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- cyclohexyl CH2HNO.sub.3                                                                              170-174               88  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- phenyl     N   HCl.HNO.sub.3                                                                         116-131                                                               H.sub.2 O                     89  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- phenyl     N   2HNO.sub.3                                                                             98-114               90  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- phenyl     CH  2HCl.H.sub.2 O                                                                        resin                 91  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-tolyl    N   2HNO.sub.3                                                                            148-154               92  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-tolyl    CH2HNO.sub.3                                                                              196-200               93  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-fluoromethyl                                                                           N   2HNO.sub.3.H.sub.2                                                                    131-139               94  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-fluoromethyl                                                                           CH2HNO.sub.3                                                                               160-165              95  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N   2H.sub.2 SO.sub.4                                                                     172-175               96  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      193-200               97  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 SO --                                                                              -- 4-chlorophenyl                                                                           CH--        viscous oil           98  2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 SO.sub.2                                                                         --                                                                              -- 4-chlorophenyl                                                                           CH--        viscous oil           99  4-chlorophenyl                                                                          H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N--          82                   100 4-bromophenyl                                                                           H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH--        viscous oil           101 tolyl     H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH--        viscous oil           102 4-methoxyphenyl                                                                         H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N--         viscous oil           103 thienyl   H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH--        viscous oil           104 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-bromophenyl                                                                            N   2HNO.sub.3                                                                            154-165               105 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-bromophenyl                                                                            CH2HCl      178-187               106 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- phenolyl   N   2HCL.1.5H.sub.2 O                                                                     108-112               107 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- phenolyl   CH2HCl      202-216               108 biphenylyl                                                                              H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH2HCl      190-192               109 1-naphthyl                                                                              H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-fluorophenyl                                                                           CHHCl       153-156               110 1-naphthyl                                                                              CH.sub.3                                                                         --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-fluorophenyl                                                                           CH2HCl      175-190               111 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                               --                                                                              2,6-dichlorophenyl                                                                       N   2HNO.sub.3                                                                            142-150               112 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2,6-dichlorophenyl                                                                       CH2HNO.sub.3                                                                              180-190               113 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-naphthyl N   2HNO.sub.3                                                                            160-165               114 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-naphthyl CH2HNO.sub.3                                                                              196                   115 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-pyridyl  N--         viscous oil           116 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-pyridyl  CH--        viscous oil           117 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 2-pyridyl  CH2HNO.sub.3                                                                              178-179               118 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-pyridyl  N--         viscous oil           119 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-pyridyl  CH3HCl.2.5  deliquescent                                                      H.sub.2 O   resin                 120 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  1 -- phenyl     N   2HNO.sub.3                                                                            138-147               121 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  1 -- phenyl     CH2HNO.sub.3                                                                              128-137               122 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  1 -- 4-chlorophenyl                                                                           N   2HNO.sub.3                                                                             95-111               123 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 S  1 -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              108-133               124 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.4 --                                                                 O  --                                                                              -- H          N   --      84-85                 125 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.4 --                                                                 O  --                                                                              -- H          CH--        viscous oil           126 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.4 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           N   2HNO.sub.3                                                                            72-78                 127 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.4 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              186-193               128 4-chlorophenyl                                                                          H  --(CH.sub.2).sub.5 --                                                                 O  --                                                                              -- H          N   --       47                   129 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.5 --                                                                 O  --                                                                              -- H          N   --      viscous oil           130 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.3 --                                                                 O  --                                                                              -- H          CH--        viscous oil           131 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.5 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           N   2HNO.sub.3                                                                            140-140               132 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.5 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              156-161               133 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.6 --                                                                 O  --                                                                              -- H          N   --      viscous oil           134 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.6 --                                                                 O  --                                                                              -- H          CH--        viscous oil           135 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.6 --                                                                 O  --                                                                              -- 4-chlorophenyl                                                                           N   2NHO.sub.3                                                                            140-160               136 2,4-dichlorophenyl                                                                      H  --(CH.sub.2).sub.6 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           N   2HCl    waxy                  137 2,4-dichlorophenyl                                                                      H  decylene                                                                              O  --                                                                              -- 4-chlorophenyl                                                                           N   2HNO.sub.3                                                                            131-144               138 2,4-dichlorophenyl                                                                      H  decylene                                                                              O  --                                                                              -- 4-chlorophenyl                                                                           CH2HNO.sub.3                                                                              114-124               139 1-naphthyl                                                                              H  --(CH.sub.2).sub.3 --                                                                 S  --                                                                              -- 4-chlorophenyl                                                                           CHHCl       172-176               __________________________________________________________________________

EXAMPLE A Tablet containing 200 mg of active compound for oraladministration

2 g of compound No. 96 and 1 g of lactose were granulated with 1 ml of10% strength aqueous polyvinylpyrrolidone K25 solution. The mixture wasforced through a screen of mesh size 3-5 mm and was dried. This driedmixture was homogenized through a screen of mesh size 0.8-1.25 mm andthen mixed with 0.58 g of microcrystalline cellulose (Avicel PH102), 30mg of Na carboxymethyl starch and 2 mg of magnesium stearate. Theresulting mixture was compressed to 10 tablets.

EXAMPLE B 1% strength solution for topical treatment

Sufficient polyethylene glycol 400 was added to a solution of 1 g ofcompound No. 96 in 50 ml of purified water to produce a total of 100 mlof solution.

EXAMPLE C 1% ointment for topical treatment

66 g of liquid petrolatum were melted on a waterbath with 3.5 g of Alfol16 (cetyl alcohol) and 0.1 g of cholesterol, and a solution of 1 g ofcompound No. 96 in 29.4 g of purified water was added. While coolingslowly, this mixture was homogenized to produce 100 g of ointment.

EXAMPLE D 1% injection solution (ampoules containing 100 mg of activecompound)

3 g of compound No. 96 and 0.3 g of a mixture of 2 parts of methylp-hydroxybenzoate and one part of propyl p-hydroxybenzoate weredissolved and made up to 300 ml with water for injection, and thesolution was filtered through a membrane filter of pore size 0.2 μm tosterilize and remove particles and then dispensed into 10 ml ampoulesunder aseptic conditions.

EXAMPLE E

The antimycotic activities of the compounds were measured by in vitrodetermination of the minimum inhibitory concentration (MIC) for yeasts,molds and dermatophytes.

6 dermatophytes, 2 yeasts and 4 molds were used for testing with fungi,as follows:

    ______________________________________                                        Trichophyton mentagrophytes                                                                           (Tri.me.)                                             Trichophyton rubrum     (Tri.ru.)                                             Trichophyton verrucosum (Tri.ve.)                                             Microsporum canis       (Mi.can.)                                             Epidermophyton floccosum                                                                              (Ep.flo.)                                             Microsporum gypseum     (Mi.gyp.)                                             Candida albicans        (C.alb.)                                              Candida tropicalis      (C.trop.)                                             Aspergillus fumigatus   (Asp.fu.)                                             Mucor mucedo plus       (Muμsup. +)                                        Mucor mucedo minus      (Mu.mu.sup.-)                                         Absidia ramosa          (Abs.ra.)                                             ______________________________________                                    

The minimum inhibitory concentration (MIC) was determined in serialdilution tests in test tubes. The volume of the liquid nutrient mediumin each test tube was 4.5 ml.

The substances were dissolved in DMSO and diluted with sterile distilledwater to 10 concentrations (100, 50, 25, 12.5, 6.25, 3.12, 1.56, 0.78,0.39 and 0.19 μg/ml). 0.5 ml of each of these dilution steps was addedto liquid nutrient medium. Thus, a constant concentration of solvent inall the nutrient media was ensured, irrespective of the active compoundconcentration.

A comparison solution which contained only the solvent in appropriateconcentration was included when carrying out each of the tests.

The individual strains were maintained on Sabouraud/beerwort agar slantsand, before they were used in a test, they underwent a passage on amodified Sabouraud liquid nutrient medium. The strains were thenharvested, washed and converted into a suspension of McFaerland 3 in thecase of yeasts and molds and of McFaerland 4-5 in the case ofdermatophytes.

The amount of material inoculated (inoculum) was 100 μl/test tube(inoculated densities: yeasts about 10³ /ml, molds about 10⁴ /ml,dermatophytes about 10⁴ /ml). The pH of the liquid nutrient medium was6.0. After inoculation had taken place the fungi were incubated at 22°C. for 14 days.

The MIC was then determined. The concentration step at which growth wasno longer visible on macroscopic inspection was used for thedetermination of the MIC. The comparison substance used was1-(2-(2,4-dichlorophenyl)-2-(2,4-dichlorophenylmethoxy)ethyl)-1H-imidazole(compound A).

                                      TABLE II                                    __________________________________________________________________________    MIC values (μg/ml)                                                         Compound                                                                            Tri.                                                                             Tri.                                                                             Tri.                                                                             Mi.                                                                              Ep.                                                                              Mi.                                                                              C. C. Asp.                                                                             Mu.                                                                              Mu.                                                                              Abs.                                   No.   me.                                                                              ru.                                                                              ve.                                                                              can                                                                              flo                                                                              gyp                                                                              alb                                                                              trop                                                                             fu.                                                                              mu+                                                                              mu-                                                                              ra.                                    __________________________________________________________________________    34    0,78                                                                             0,78                                                                             0,78                                                                             0,78                                                                             0,78                                                                             0,78                                                                             3,12                                                                             3,12                                                                             6,25                                                                             3,12                                                                             3,12                                                                             6,25                                   37    1,56                                                                             1,56                                                                             1,56                                                                             6,25                                                                             1,56                                                                             0,78                                                                             6,25                                                                             6,25                                                                             6,25                                                                             6,25                                                                             6,25                                                                             12,5                                   39    6,25                                                                             6,25                                                                             6,25                                                                             12,5                                                                             12,5                                                                             6,25                                                                             25,0                                                                             12,5                                                                             12,5                                                                             12,5                                                                             12,5                                                                             25,0                                   40    6,25                                                                             3,12                                                                             3,12                                                                             3,12                                                                             6,25                                                                             3,12                                                                             6,25                                                                             6,25                                                                             12,5                                                                             12,5                                                                             12,5                                                                             12,5                                   90    25,0                                                                             1,56                                                                             1,56                                                                             3,12                                                                             3,12                                                                             3,12                                                                             6,25                                                                             3,12                                                                             3,12                                                                             6,25                                                                             3,12                                                                             12,5                                   92    0,78                                                                             0,78                                                                             0,78                                                                             3,12                                                                             0,78                                                                             0,78                                                                             12,5                                                                             12,5                                                                             0,78                                                                             0,78                                                                             3,12                                                                             6,25                                   94    6,25                                                                             0,78                                                                             0,39                                                                             6,25                                                                             3,12                                                                             3,12                                                                             12,5                                                                             6,25                                                                             12,5                                                                             12,5                                                                             12,5                                                                             6,25                                   96    0,39                                                                             0,19                                                                             0,39                                                                             0,39                                                                             0,19                                                                             0,39                                                                             0,39                                                                             0,78                                                                             0,78                                                                             1,56                                                                             1,56                                                                             1,56                                   2     12,5                                                                             0,19                                                                             0,39                                                                             1,56                                                                             6,25                                                                             3,12                                                                             3,12                                                                             1,56                                                                             3,12                                                                             12,5                                                                             25,0                                                                             3,12                                   1     0,39                                                                             0,39                                                                             0,30                                                                             1,56                                                                             0,78                                                                             0,39                                                                             3,12                                                                             1,56                                                                             1,56                                                                             6,25                                                                             6,25                                                                             3,12                                   112   3,12                                                                             3,12                                                                             3,12                                                                             12,5                                                                             3,12                                                                             3,12                                                                             6,25                                                                             6,25                                                                             12,5                                                                             6,25                                                                             12,5                                                                             12,5                                   114   3,12                                                                             1,56                                                                             1,56                                                                             0,78                                                                             3,12                                                                             3,12                                                                             3,12                                                                             6,25                                                                             0,78                                                                             6,25                                                                             3,12                                                                             6,25                                   3     6,25                                                                             6,25                                                                             6,25                                                                             1,56                                                                             1,56                                                                             6,25                                                                             3,12                                                                             0,78                                                                             25,0                                                                             6,25                                                                             6,25                                                                             50,0                                   132   0,78                                                                             3,12                                                                             6,25                                                                             12,5                                                                             0,78                                                                             3,12                                                                             6,25                                                                             3,12                                                                             6,25                                                                             0,78                                                                             3,12                                                                             6,25                                   14    12,5                                                                             6,25                                                                             12,5                                                                             12,5                                                                             3,12                                                                             6,25                                                                             12,5                                                                             12,5                                                                             100                                                                              12,5                                                                             6,25                                                                             100                                    33    25,0                                                                             3,12                                                                             3,12                                                                             6,25                                                                             3,12                                                                             6,25                                                                             12,5                                                                             6,25                                                                             25,0                                                                             6,25                                                                             3,12                                                                             25,0                                   36    25,0                                                                             6,25                                                                             12,5                                                                             100                                                                              12,5                                                                             6,25                                                                             25,0                                                                             12,5                                                                             100                                                                              12,5                                                                             50,0                                                                             100                                    52    6,25                                                                             3,12                                                                             3,12                                                                             3,12                                                                             3,12                                                                             3,12                                                                             12,5                                                                             6,25                                                                             6,25                                                                             3,12                                                                             12,5                                                                             100                                    62    1,56                                                                             3,12                                                                             1,56                                                                             3,12                                                                             0,78                                                                             3,12                                                                             6,25                                                                             3,12                                                                             1,56                                                                             3,12                                                                             3,12                                                                              50                                    67    100                                                                              25,0                                                                             6,25                                                                             50,0                                                                             100                                                                              25,0                                                                             100                                                                              50,0                                                                             100                                                                              50,0                                                                             50,0                                                                             100                                    68    25,0                                                                             50,0                                                                             6,25                                                                             12,5                                                                             25,0                                                                             25,0                                                                             50,0                                                                             25,0                                                                             100                                                                              6,25                                                                             12,5                                                                             100                                    72    25,0                                                                             3,12                                                                             1,56                                                                             25,0                                                                             6,25                                                                             6,25                                                                             3,12                                                                             3,12                                                                             3,12                                                                             6,25                                                                             6,25                                                                             100                                    93    12,5                                                                             6,25                                                                             6,25                                                                             25,0                                                                             25,0                                                                             25,0                                                                             100                                                                              25,0                                                                             100                                                                              25,0                                                                             25,0                                                                             100                                    95    3,12                                                                             1,56                                                                             3,12                                                                             6,25                                                                             0,78                                                                             3,12                                                                             12,5                                                                             12,5                                                                             12,5                                                                             3,12                                                                             3,12                                                                             100                                    99    6,25                                                                             3,12                                                                             3,12                                                                             12,5                                                                             6,25                                                                             3,12                                                                             6,25                                                                             12,5                                                                             100                                                                              12,5                                                                             6,25                                                                             100                                    104   25,0                                                                             6,25                                                                             12,5                                                                             100                                                                              12,5                                                                             6,25                                                                             25,0                                                                             12,5                                                                             100                                                                              12,5                                                                             50,0                                                                             100                                    126   50,0                                                                             6,25                                                                             3,12                                                                             25,0                                                                             12,5                                                                             3,12                                                                             25,0                                                                             12,5                                                                             25,0                                                                             12,5                                                                             25,0                                                                             100                                    67    50,0                                                                             6,25                                                                             6,25                                                                             25,0                                                                             50,0                                                                             12,5                                                                             25,0                                                                             50,0                                                                             25,0                                                                             12,5                                                                             12,5                                                                             50,0                                   40    6,25                                                                             3,12                                                                             3,12                                                                             12,5                                                                             3,12                                                                             3,12                                                                             6,25                                                                              25                                                                              6,25                                                                             12,5                                                                              25                                                                              12,5                                   100   6,25                                                                             3,12                                                                             6,25                                                                             6,25                                                                             6,25                                                                             6,25                                                                             3,12                                                                             12,5                                                                             6,25                                                                             12,5                                                                              25                                                                              6,25                                   105   0,10                                                                             0,10                                                                             0,10                                                                             0,78                                                                             0,10                                                                             0,39                                                                             3,12                                                                             3,12                                                                             0,39                                                                             3,12                                                                             3,12                                                                             12,5                                   108   0,78                                                                             1,56                                                                             0,78                                                                             6,25                                                                             0,78                                                                             3,12                                                                             12,5                                                                             12,5                                                                             3,12                                                                             6,25                                                                             6,25                                                                              50                                    139   3,12                                                                             1,56                                                                             1,56                                                                             1,56                                                                             3,12                                                                             1,56                                                                             3,12                                                                             12,5                                                                             3,12                                                                             3,12                                                                             3,12                                                                             3,12                                   103   12,5                                                                             3,12                                                                             3,12                                                                              25                                                                              3,12                                                                             6,25                                                                             12,5                                                                              25                                                                              12,5                                                                             12,5                                                                             12,5                                                                              25                                    56    3,12                                                                             1,56                                                                             1,56                                                                             12,5                                                                             6,25                                                                             3,12                                                                             12,5                                                                             3,12                                                                             0,78                                                                             1,56                                                                             0,78                                                                             6,25                                   65    6,25                                                                             0,78                                                                             1,56                                                                             1,56                                                                             3,12                                                                             3,12                                                                             3,12                                                                             1,56                                                                             3,12                                                                             6,25                                                                             6,25                                                                             3,12                                   60    6,25                                                                             0,78                                                                             1,56                                                                             1,56                                                                             3,12                                                                             3,12                                                                             3,12                                                                             1,56                                                                             6,25                                                                             3,12                                                                             1,56                                                                             6,25                                   A     1,56                                                                             6,25                                                                             6,25                                                                             6,25                                                                             1,56                                                                             3,12                                                                             12,5                                                                             12,5                                                                             3,12                                                                             12,5                                                                             12,5                                                                             12,5                                   __________________________________________________________________________

EXAMPLE F

Determination of the lethal dose of1-(2-(2,4-dichlorophenyl)-2-(3-(4-chlorophenylthio)propylamino)ethyl)-1H-imidazoledihydrochloride (compound No. 96) in mice and rats on administrationonce.

In each case, oral doses of 0, 500, 1,000 and 3,000 mg/kg of body weightwere administered to four groups of female and male animals.

(Control: double-distilled water)

The following clinical signs were observed.

    ______________________________________                                        Mice:        Inactivity, convulsions                                          Rats:        Inactivity, ruffled fur, convulsions                                          LD.sub.100                                                       Mice                                                                          female       >1,000 mg/kg                                                                              <3,000 mg/kg                                         male         >500 mg/kg  <1,000 mg/kg                                         Rats                                                                          female       >500 mg/kg  <1,000 mg/kg                                         male         >1,000 mg/kg                                                                              <3,000 mg/kg                                         ______________________________________                                    

EXAMPLE G

Determination of the LD₅₀ of1-(2-(2,4-dichlorophenyl)-2-(3-(4-chlorophenylthio)propylamino)ethyl)-1H-imidazoledihydrochloride (compound No. 96) in mice and rats by i.v.administration. In each case, 0 (0.9% NaCl solution), 12.5, 25.0, 50.0and 100 mg/kg of body weight were injected i.v. into 5 groups of femaleand male animals.

The following clinical signs were observed.

    ______________________________________                                        Mice:        Inactivity, necrotic tail                                        Rats:        Inactivity, necrotic tail, convulsions                                        LD.sub.50                                                        Mice                                                                          female       84.1 (20.8-340.0) mg/kg                                          male         42.0 (13.9-127.5) mg/kg                                          Rats                                                                          female       56.1 (35.4-89.1) mg/kg                                           male         70.7 mg/kg                                                       ______________________________________                                    

EXAMPLE H

Compound No. 96 was investigated for its potential to cause genemutations in five Salmonella typhimurium strains TA 1535, TA 1537, TA1538, TA 98 and TA 100.

The following concentrations were tested, both with metabolic activator(S 9 mix) and without metabolic activator.

I: 10, 33.3, 100.0, 333.3, 1,000 μg/plate

II: 3.3, 10, 33.3, 100, 333.3 μg/plate

No mutagenic activity whatever was observed, either with or withoutmetabolic activator.

What we claim is:
 1. A triazole derivative of the formula: ##STR8## inwhich Ar is thienyl or is phenyl, biphenylyl or naphthyl, each of whichis substituted by halogen, lower alkyl or lower alkoxy, R¹ is hydrogenor lower alkyl, Alk is straight-chain or branched alkylene having 1 to10 carbon atoms, Y is oxygen, sulfur, sulfinyl or sulfonyl, n is zero 1or 2, Z is oxygen sulfur or sulfinyl, m is zero or 1, R³ is hydrogen,straight-chain or branched alkyl having 1 to 12 carbon atoms,cyclohexyl, or is phenyl which is optionally substituted by hydroxyl,halogen, trifluoromethyl, lower alkyl or lower alkoxy, or is biphenylyl,pyridyl or is naphthyl which is optionally substituted by halogen, andR² is hydrogen or lower alkyl, or a pharmaceutically acceptable acidaddition salt.
 2. A triazole derivative as claimed in claim 1, of theformula I in which each of R¹ and R² independently of one another ishydrogen or methyl.
 3. A triazole derivative as claimed in claim 1, ofthe formula I in which Ar is 2,4-dichlorophenyl or 4-chlorophenyl.
 4. Atriazole derivative as claimed in claim 1, of the formula I in which Alkis --(CH₂)₂ -- or --(CH₂)₃ --.
 5. A triazole derivative as claimed inclaim 1, of the formula I in which Y is oxygen or sulfur.
 6. A triazolederivative as claimed in claim 1, of the formula I in which R³ isphenyl, 4--Cl--, 4--Br, 4--I, 4-methoxy or 4-methylphenyl, 2,4-,3,4- or2,6-dichlorophenyl, 2-methyl-4-chlorophenyl, cyclohexyl or naphthyl. 7.A triazole derivative as claimed in claim 1, of the formula I in whicheach of m and n is zero.
 8. A method for the treatment or prevention ofa mycotic infection in a patient which comprises administering to thepatient an antimycotic-effective amount of a triazole derivative of theformula: ##STR9## in which Ar is thienyl or is phenyl, biphenylyl ornaphthyl each of which is substituted by halogen, lower alkyl or loweralkoxy, R¹ is hydrogen or lower alkyl, Alk is straight-chain or branchedalkylene having 1 to 10 carbon atoms, Y is oxygen, sulfur, sulfinyl orsulfonyl, n is zero, 1 or 2, Z is oxygen, sulfur or sulfinyl, m is zeroor 1, R³ is hydrogen, straight-chain or branched alkyl having 1 to 12carbon atoms, cyclohexyl, or is phenyl which is optionally substitutedby hydroxyl, halogen, trifluoromethyl, lower alkyl or lower alkoxy, oris biphenylyl, pyridyl or is naphthyl which is optionally substituted byhalogen, and R² is hydrogen or lower alkyl, or a pharmaceuticallyacceptable acid addition salt.
 9. A method as claimed in claim 8, inwhich, in the compound of formula I, each of R¹ and R², independently ofone another, is hydrogen or methyl, Ar is 2,4-dishlorophenyl or4--chlorophenyl, Alk is (CH₂)₂ -- or --(CH₂)₃ --, Y is oxygen or sulfur,R³ is phenyl, 4--Cl--, 4--Br--, 4--I--, 4--methoxy- or 4-methylphenyl,2,4-, 3,4-, or 2,6-dichlorophenyl, 2-methyl-4-chlorophenyl, cyclohexylor naphthyl, and each of m and n is zero.